Top Doctors 2006: Who Wants to Live Forever?

A Drexel professor and a Mount Airy couple may have found the secret to extending life, but does anyone truly want to be 100?

What do you bring to dinner with members of the Calorie Restriction Society? (Motto: “Fewer calories. More life.”) Not dessert. Or cheese. But do they drink? Are flowers superfluous? I decided on coffee, then sat with it outside their Mount Airy twin, killing time until just before 7 p.m., the precise hour that one of my hosts insists on eating. I found such mealtime rigidity odd for someone who’s 35, not 75. But then, I might like to dine promptly, too, if I were six feet tall, 115 pounds, and waiting to consume the biggest meal (all 629 calories of it!) of my day.

And I was prepared for weird. This was a story that started, originally, with a professor at Drexel trying to create an “ageless mouse,” which led, for the moment anyway, to a couple who think they can live “indefinitely”—provided they don’t eat much. That the professor and the couple are both on the forefront of anti-aging research came as more of a surprise. Get in the requisite eye-rolling at those hoping to renegotiate the terms of their mortality, but then take a look at the news. Recent genetic breakthroughs are making the idea that we can control when and how we age a real possibility—and just in time for those meddlesome, graying baby boomers who find their thoughts suddenly turning to a fix. The result—part scientific leap, part societal demand—is a shift in thinking and a rapidly growing trend. As scientists ponder how to manipulate genes to delay getting older, new anti-aging medicines are leapfrogging past the lab work. Boutique docs with high-priced services are prescribing cocktails of treatments promising to make former flower children feel more like Generation Xers (without all the angst).

But while $2,500-a-session doctors in Southern California are extolling the virtues of injecting yourself with human growth hormone and of, yes, eating less, what’s going on in our city could prove the meatier backbone to this relatively unproved, increasingly trendy medicine. It could also take the piss out of at least some of what they’re hawking. Cali may have the newfound optimism, but as it turns out, Philly may have the next important link to the science. And, as always, a few of the more interesting characters.

Which brings us to dinner. Specifically, dinner with April Smith and Michael Rae, two prominent members of the Calorie Restriction Society, which I’d looked into after first talking with Dr. Christian Sell, the guy at Drexel with the could-be-ageless mouse. Dr. Sell isn’t himself a proponent of the low-cal longevity diet for humans, and his mice aren’t being starved to live longer (though the oldest mice on record were). But he considers the caloric restriction effect “still the gold standard” in anti-aging research, and his own experiment is a related offshoot. The effect, discovered way back in 1934, is quite simple: If you feed mice a lot less, they live a lot longer. And so what happens when you do that to humans?

Turns out, the humans at the house in Mount Airy were both redheads. They were both kind of pale (except for Rae’s hands, which have turned orange from all the beta carotene he ingests). And yeah, they were both really skinny, though Smith looked kind of good like that. They also seemed madly in love: There were lingering kisses over the arugula-and-beet salad, and an oddly passionate moment described as “our version of grace.” (Eyes locked, forks rhythmically clinking against their plates, they exchanged an intense responsory about, as well as I could make out, the fortifying powers of food and the joy of sharing it.) And this love seemed, as it often does, to have much to do with hunger, and control. At the end of our evening’s voluminous feast, one I couldn’t hope to finish (there are, apparently, no calories in vegetables?), Rae made quiet mouth sounds of pleasure, and upended his glass, searching poignantly for the last phantom drop of his three ounces of pinot before lowering his sinewy neck, puppy-like, and asking, “Am I done?” “He never knows,” Smith explained. “I’m totally in control of his dinner.” And by that, she meant she’d measured it, to the mushroom, and in planning the recipes in the first place used his computer software to make sure they perfectly fit his stringent fat/carb/­protein ratios and total calorie count for the day. (Who’s the boss now?)

But the point here is not so much how, or how oddly, they eat. The point is that they want to live a really, really long time and “be younger for more of it.” Rae started messing around with this stuff after college, in Calgary, during one of those awful years of your 20s that you later pretend didn’t exist. He pushed himself too hard. He didn’t take care of himself. And his boyish, “indefatigable immune system” took its first adult hit. He got sick. Run-down. Must be aging, he thought, with the misguided intensity of someone in his 20s. And his scientific mind began hunting for solutions. First, he looked into megavitamins, the anti-aging craze at the time, believed to target free-radical damage. That, he ultimately decided, was all nonsense.

But the studies on caloric restriction he came upon caught his interest; it upped the lifespan of animals like mice by as much as 40 percent. He kept reading, and thinking about it, and weighing the potentially devastating social consequences of making an already thin guy skinny. A few years later, he started to cut back, bit by bit, to where he is today: elbows like knife points, consuming 1,843 calories a day, the lowest number he feels he can tolerate relatively comfortably, nutrients measured to the milligram to ensure adequate nutrition. Smith, who readily admits she’s more of a moderate CR follower, jumped into it more impulsively. Two years ago, at a party, she looked around at all the sagging, slightly plump faces—feeling, at 29, already slightly saggy and plump herself—and decided, right then and there, that she “just wasn’t going to age anymore.” Since then, she’s become a voice for the movement through her blog, a “CR diary” that chronicles everything from her joy in weight loss to her love of Rae in amusing, if occasionally smug, fashion. On a period missed because she eats so little: “Yipppeeee!” On the horrors of “gak,” or junk food: “You notice when you start CR that you no longer feel comfortable giving people gifts of sugar-filled high-calorie gak. You actually feel like you’re killing them.”

Since that landmark 1934 study, caloric restriction experiments have been repeated with other animals, and there’s a fairly widely accepted evolutionary theory about why fewer calories equals more life. It’s believed that a near-starvation diet triggers genes that produce hormones that slow down an animal’s metabolic and other bodily functions until the environmental stress supposedly causing the starvation—a famine, say—lifts. This slowdown also seems to stop time on a cellular level. But for a long time, the basic effect was only an observation. It sat on the shelf with a couple of other classics, like the correlation between size and lifespan (smaller animals within the same species—chihuahuas vs. Labradors—tend to live longer), or the effect of when an animal reproduces. (In the 1970s, scientist Michael Rose bred 12 generations of fruit flies, delaying reproduction until later and later ages with each subsequent line. And the later generations of flies lived significantly longer.)

What’s possibly seismic now is that researchers like Christian Sell at Drexel are getting closer not only to identifying, but to actually manipulating what genes are involved in these earlier field notes. For instance, Sell’s work with midget mice examines the effect on lifespan when you knock out a gene that reduces a specific growth hormone. To him, the progression, and proliferation, of longevity research is the important thing. “Now we’re starting to have all these different types of mice that have different genetic differences that influence hormones in different ways,” he says. “So you can start to ask questions like which ones are responsible for the caloric restriction effect, or which ones are responsible for different aspects of extended life, like, say, tumor reduction.”

And that amounts to things really heating up in a field that seems to have crept along for decades. It was only 15 years ago, after all, that Vincent Cristofalo, now at Lankenau Medical Research Center in Wynnewood, helped discover something that today seems pretty basic: Human cells don’t divide forever in a petri dish. Unlike, say, cancer, they naturally age and die. While much of anti-aging research and its recent genetic breakthroughs is closely related to well-heralded advances in diseases like cancer or Alzheimer’s, the field was something of a scientific stepchild for decades. That’s partly a result of our own attitudes, our acceptance of what we see as the depressing but unavoidable course of nature. Ten more heart-healthy years? Sign us up. A “cure” for aging? That’s just silly. Absent a public push for an anti-­aging pill, there’s been no billion-dollar incentive for the pharmaceutical industry to drill down on anti-aging efforts the way it does on age-related disease.

Which leaves scientists with the burden to show they can treat old age itself. And which leaves Rae, and other geeky life-­extensionist types, with little but his own admittedly “crude intervention”: staying out of restaurants and away from those “evil grains” until something better comes along. If she had only 24 more hours to live, Smith says, she’d spend it on CR. Rae, however, is not so sure. Yes, he insists, clearing his raggedy throat again, he feels great, and hasn’t been sick in three years. Still, he thinks his diet is a giant hassle if all it gets him and April is a measly 20 more years apiece. Twenty more years isn’t enough? You see, he explains, the plan is to use CR to hold on until the first big phase of biomedical anti-aging treatments is available. “We’re hoping to make it,” Smith chimes in. If they do, and then hold on some more, until the next wave of advances, and the next, “We’ll eventually be on track to an indefinite life-span,” Rae says.

As they talk, I start to imagine bright lights illuminating the landing gear of a rescue spaceship, and, through the window, the Rip Van Winkle-like beard of their leader, Cambridge professor Aubrey de Grey. De Grey is in England, but Rae works for him here, as his research and writing assistant, and considers him a genius, “the person responsible more than any other human being for our transition to an ageless future, to not spending every day deteriorating from internal rot.” And the guy is also just a whole lot of fun, Smith notes. If only he would practice CR, she laments, so he could be here with them forever.

That their guru is brilliant I don’t doubt, as I try to grasp his website’s content. I hope it will suffice to say that he has a lot of interesting, very scientific theories about how to target all that age-inducing cellular “junk” produced by daily metabolic processes. (Caloric restriction isn’t part of his plan; he’s not against it, he just doesn’t see it buying humans and other longer-lifespan animals more than a couple of extra years.) When he’d zap that cellular waste is critical to his theory. Prevention, for instance, isn’t his bag. His attack, which would involve things like vaccines, stem cells and gene therapy, gears up just before the waste hits a later-in-life, point-of-no-return threshold.

Over the phone, he’s also pretty engaging on all the social repercussions we’d have to start debating if we actually lived to 1,000. (Do you ever get to retire? If things get too crowded, do we all agree to off ourselves at some point? Who gets to have kids? When? What about boredom, life sentences, near-immortal tyrants?) As a society, we don’t get into all of that very often, de Grey says, because our limiting view of aging tends to stunt the conversation before it begins. Where we go wrong, apparently, is in believing “that aging is in some way different from all other aspects of nature that we feel entitled to manipulate. We feel it’s inviolate.” Acceptance, he says, yields inaction. We “invent really quite illogical reasons to defend aging,” and “spend what little life one has not thinking about this grim, ghastly and horrible reality until its symptoms are unavoidable.”

Denial, plus cheeseburgers. Sounds like a pretty good plan to me. But de Grey would prefer we join forces in a worldwide effort to combat this scourge of our grandparents—save your votes for those who’ll declare war on the menace!—whether or not his own theories are proven to work. He gives them about a 50/50 chance. If the science worked out just right, he says, and the money became available to create the vaccines and genetic interventions he’s outlined, his targeted, age-zapping fixes could be available in 25 years: Spaceship landing! Of course, that might not happen. And if it doesn’t, he’d like more minds like his funded in their research. That’s why he dreamed up the Methuselah Mouse Prize, which, in the spirit of great scientific prizes of the past—the ones that inspired Lindbergh’s flight, and North Pole exploration—challenges scientists to create an “ageless mouse,” promising a grand prize of $3 million to anyone who does.

Which brings us back to those mice at Drexel. But before we get into any of the specific reasons why these mice are contenders for de Grey’s prize and are scientifically important, let me note that they’re really, really cute, these little guys, running around in their shoebox-size cages, sitting on their ­fingertip-size young, lapping at their giant water bottles. No Napoleonic complex here! You can make this kind of lame observation to Sell, and he’ll back you up: Turns out their lack of a specific growth hormone—what makes them small—has a fringe benefit of making them more docile, and friendlier, than usual. Minus the size issues, Dr. Sell shares a few traits with the unique crew of rodents he wakes up every day hoping is still kicking. For one thing, with his sandy flop of hair, piercing blue eyes and fat-free physique, he looks truly, ridiculously young for 47. And he’s awfully nice, and laid-back. He defuses all of the hype about aging elixirs with a laugh, yet presents the science of what he’s doing so clearly and calmly that you become intrigued, too. Sell moved from Lankenau to Drexel last fall in part because he likes to teach, and he didn’t mind taking the time to provide a little background, and dwarf mouse trivia.

Dwarfs were obvious guinea pigs for aging research, given that whole thing about smaller animals in the same species tending to live longer. Ironically, though, when dwarf mice were first created for study in labs, they were believed to be a bust. They were born, and within months—oops!—they died. Turned out they were just really, really cold, and needed to be assigned a full-size cage buddy for warmth. Sell’s dwarfs are slightly different; they’re actually “midi”, or medium-sized, dwarves. And while some earlier dwarf mice had the misfortune of being sterile, Sell’s, he found, can reproduce—like crazy, apparently, as a video of one of the old guys humping a younger female seems to show. (“Just a silly thing we made in the lab.”) And it looks like they can reproduce later in life, which could be important in the aging equation.

So far, the oldest of his mice have lived nearly three years, and they average between 2.5 and three years—an increase of up to 50 percent over the normal average. He jokes with Andrzej Bartke of the Southern Illinois University School of Medicine—whose growth-hormone-limited mouse lived to a week shy of five years, a relative eternity—that he might soon beat that record. Sell’s work fits in with other experiments, like Bartke’s, that target growth hormone and its effect on aging, but he’s examining a more precise genetic link (and related hormone). The research is adding up to indicate that the scarcity of some growth hormones, especially early in life, accounts for the longevity effect. And that in itself has big implications. So, I ask, the doctors recommending injections of human growth hormone are in fact doing the opposite of what science shows might slow down aging? Exactly, Sell says.

The hormone Sell’s genetically engineered mice lack is called IGF, and it influences everything from insulin production to cell division. Sell started studying it as a cancer, not an aging, researcher. At the time, he was at Lankenau, trying to understand why older cells, unlike younger ones, stop responding to IGF and therefore stop multiplying. If he could find the off switch, perhaps a similar one could be created for “infinite,” or always-multiplying, cancer cells. In the process, he looked up from his petri dish and realized that this could be a bridge from cancer to the aging field, since his work on the cellular level was clearly starting to overlap with what the guys down the hall were studying in aging. So he searched the literature, looking for experiments that for some unrelated reason might have produced mice without IGF. He found one, called up research giant Genentech, and asked if that line of embryos still existed. Sure enough, they were sitting in cold storage at the scientific mouse repository at Jackson Laboratory in Bar Harbor, Maine. Sell got a grant, and several in-vitro fertilizations later, he had his little mice, ready for testing.

All he has to do now is wait and see if his hunch is correct, if his mice are Methuselahs—and, as he puts it, stake his career on jumping from relatively safe cancer research to the much shakier field of aging. Funding is the elephant in any lab, but when you’re in “aging,” the “slipperiness of the field” makes the money hunt that much harder, explains Dr. Arlan Richardson, who’s collaborating with Sell on an NIH grant, and who’s also one of the few academics to have successfully built a well-endowed aging institute. (His is at the University of Texas Health Science Center at San Antonio.) It’s inherently frustrating, Richardson says, to be in a field where just defining what you’re studying is tricky: “What is aging? When does it start? Everyone knows the difference if you look at an old person and a young one. But when we look at the biology, it’s not clear-cut what pathways are critical to aging.” Even something as rudimentary as when aging starts, he says, is up in the air, and his thinking on that score has changed. He used to believe that getting old began at birth, but he now flips the hourglass over when an animal starts to reproduce. It’s just a theory, he says, but it jibes with what many scientists now accept as an evolutionary basis for aging. Our development, and the huge amount of energy and cellular processes required to drive it, is focused on reproduction and perpetuating the species. In evolution’s eyes, once we’ve pumped out some offspring, we’re expendable; our system therefore neglects to focus on later-in-life repair.

Which brings us back to IGF. It’s involved in so many different cell processes (growth, reproduction, metabolism) that it could prove a critical link between several theories about aging. 60 Minutes went so far as to call it the “longevity hormone” when featuring Sell and his work recently. “IGF is critical during development, and levels of it increase up to puberty,” Sell explains. “So there’s a tie between development, fertility and, eventually, lifespan, but we don’t know what those mechanisms are.” The picture that’s developing, he says, is that our life-span is dictated by developmental issues. Affect those, and you’ll change lifespan, just as evolution naturally does over thousands of years. The takeaway is clear, if years away: “We might be able to ID a window early in development and influence these hormones and get long-term benefits, and maybe stay healthier over our lifespan.”

It’s an exciting possibility, sure, but Sell’s not really all that into it on a personal level. These days, he says, he’s more worried about “sudden death by accident”—getting hit while riding his bike down the path from his home in Conshohocken to his office in Center City. Besides, he says (a couple of times), once you have kids, you really stop caring so much about your own mortality. You’re too busy. They’re so much more important than you are. Or is, hmm … is evolution just finished with you? I suggest that he should try that experiment from the ’70s—the one where that guy got generations of fruit flies to live longer by delaying their breeding—with his mice. Yeah, he’d like to, Sell says. Certainly someone should do it. But then he shrugs: With mouse lifespans being what they are, and his being what it is, well, the problem, as always, is time.

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